Clinical Focus

  • Neuromuscular Diseases
  • Neuromuscular Medicine

Academic Appointments

Professional Education

  • Board Certification: American Board of Psychiatry and Neurology, Neurology with Special Qualifications in Child Neurology (2010)
  • Fellowship: Children's National Medical Center Pediatric Infectious Diseases Fellowship (2010) DC
  • Internship: Georgetown University Hospital (2007) DC
  • Residency: Hospital Nacional de Pediatria Juan P Garrahan (2001) Argentina
  • Residency: Alejandro Posadas Hospital (1997) Argentina
  • Medical Education: Universidad de Buenos Aires (1994)

All Publications

  • Eteplirsen Treatment for Duchenne Muscular Dystrophy: A Qualitative Patient Experience Study. Advances in therapy Iff, J., Carmichael, C., McKee, S., Sehinovych, I., McNeill, C., Tesi-Rocha, C., Henricson, E., Muntoni, F., Kitchen, H. 2024


    INTRODUCTION: Duchenne muscular dystrophy (DMD) is characterized by rapid functional decline. Current available treatment options aim to delay disease progression or stabilize physical function. To aid in healthcare providers' understanding of the symptoms of disease that impact patients' experience, this study explored children's physical functioning, activities of daily living (ADLs), and health-related quality of life (HRQoL) after receiving eteplirsen, a weekly infusion indicated for individuals with DMD with exon51 skip-amenable mutations.METHODS: Fifteen caregivers of male individuals with DMD participated in a 60-min, semi-structured interview. Open-ended questioning explored changes in the children's condition or maintenance in abilities since eteplirsen initiation.RESULTS: Children with DMD (age 7-15years [mean 10.9]; steroid treatment at interview, n=8; time since eteplirsen initiation 3-24months [mean 14.9]) were described by caregivers as ambulatory (n=9) and non-ambulatory (n=6). Caregivers of ambulatory children reported improvements or maintenance of walking ability (n=7/9), running (n=6/9), and using stairs (n=4/9). Continued decline in using stairs was reported by two caregivers. In upper-limb functioning, improvements or maintenances in fine-motor movements were reported by nearly half of all caregivers (n=7/15), with one caregiver noting a continued decline. Subsequent improvements or maintenances in ADLs were described. Improvements or maintenances in fatigue (n=9/15), muscle weakness (n=7/15), and pain (n=6/15) were reported, although some caregivers described a continued decline (n=3/15 fatigue, n=1/15 muscle weakness, n=2/15 pain). Importantly, most caregivers who reported maintenances in ability perceived this as a positive outcome (n=6/9).CONCLUSION: This exploratory study indicated that most caregivers perceived improvements or maintenances in aspects of their child's physical functioning, ADLs, and HRQoL since eteplirsen initiation, which they perceived to be a positive outcome.

    View details for DOI 10.1007/s12325-024-02915-9

    View details for PubMedID 38958840

  • Assessing the Assisted Six-Minute Cycling Test as a Measure of Endurance in Non-Ambulatory Patients with Spinal Muscular Atrophy (SMA). Journal of clinical medicine Tang, W. J., Gu, B., Montalvo, S., Dunaway Young, S., Parker, D. M., de Monts, C., Ataide, P., Ni Ghiollagain, N., Wheeler, M. T., Tesi Rocha, C., Christle, J. W., He, Z., Day, J. W., Duong, T. 2023; 12 (24)


    Assessing endurance in non-ambulatory individuals with Spinal Muscular Atrophy (SMA) has been challenging due to limited evaluation tools. The Assisted 6-Minute Cycling Test (A6MCT) is an upper limb ergometer assessment used in other neurologic disorders to measure endurance. To study the performance of the A6MCT in the non-ambulatory SMA population, prospective data was collected on 38 individuals with SMA (13 sitters; 25 non-sitters), aged 5 to 74 years (mean = 30.3; SD = 14.1). The clinical measures used were A6MCT, Revised Upper Limb Module (RULM), Adapted Test of Neuromuscular Disorders (ATEND), and Egen Klassifikation Scale 2 (EK2). Perceived fatigue was assessed using the Fatigue Severity Scale (FSS), and effort was assessed using the Rate of Perceived Exertion (RPE). Data were analyzed for: (1) Feasibility, (2) Clinical discrimination, and (3) Associations between A6MCT with clinical characteristics and outcomes. Results showed the A6MCT was feasible for 95% of the tested subjects, discriminated between functional groups (p = 0.0086), and was significantly associated with results obtained from RULM, ATEND, EK2, and Brooke (p < 0.0001; p = 0.029; p < 0.001; p = 0.005). These findings indicate the A6MCT's potential to evaluate muscular endurance in non-ambulatory SMA individuals, complementing clinician-rated assessments. Nevertheless, further validation with a larger dataset is needed for broader application.

    View details for DOI 10.3390/jcm12247582

    View details for PubMedID 38137651

    View details for PubMedCentralID PMC10743820

  • The emerging spectrum of neurodevelopmental comorbidities in early-onset Spinal Muscular Atrophy. European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society Baranello, G. 2023; 48: 67-68

    View details for DOI 10.1016/j.ejpn.2023.11.006

    View details for PubMedID 38043384

  • Cerebrospinal Fluid Proteomic Changes after Nusinersen in Patients with Spinal Muscular Atrophy. Journal of clinical medicine Beaudin, M., Kamali, T., Tang, W., Hagerman, K. A., Dunaway Young, S., Ghiglieri, L., Parker, D. M., Lehallier, B., Tesi-Rocha, C., Sampson, J. B., Duong, T., Day, J. W. 2023; 12 (20)


    Disease-modifying treatments have transformed the natural history of spinal muscular atrophy (SMA), but the cellular pathways altered by SMN restoration remain undefined and biomarkers cannot yet precisely predict treatment response. We performed an exploratory cerebrospinal fluid (CSF) proteomic study in a diverse sample of SMA patients treated with nusinersen to elucidate therapeutic pathways and identify predictors of motor improvement. Proteomic analyses were performed on CSF samples collected before treatment (T0) and at 6 months (T6) using an Olink panel to quantify 1113 peptides. A supervised machine learning approach was used to identify proteins that discriminated patients who improved functionally from those who did not after 2 years of treatment. A total of 49 SMA patients were included (10 type 1, 18 type 2, and 21 type 3), ranging in age from 3 months to 65 years. Most proteins showed a decrease in CSF concentration at T6. The machine learning algorithm identified ARSB, ENTPD2, NEFL, and IFI30 as the proteins most predictive of improvement. The machine learning model was able to predict motor improvement at 2 years with 79.6% accuracy. The results highlight the potential application of CSF biomarkers to predict motor improvement following SMA treatment. Validation in larger datasets is needed.

    View details for DOI 10.3390/jcm12206696

    View details for PubMedID 37892834

  • Major Adverse Dystrophinopathy Events (MADE) Score as Marker of Cumulative Morbidity and Risk for Mortality in Boys with Duchenne Muscular Dystrophy. Progress in pediatric cardiology Kaufman, B. D., Garcia, A., He, Z., Tesi-Rocha, C., Buu, M., Rosenthal, D., Gordish-Dressman, H., Almond, C. S., Duong, T. 2023; 69


    Overlapping symptoms from cardiomyopathy, respiratory insufficiency, and skeletal myopathy confound assessment of heart failure in Duchenne Muscular Dystrophy. We developed an ordinal scale of multiorgan clinical variables that reflect cumulative disease burden-the Major Adverse Dystrophinopathy Event (MADE) Score. We hypothesized that a higher MADE score would be associated with increased mortality in boys with Duchenne Muscular Dystrophy. The Cooperative International Neuromuscular Research Group Duchenne Natural History Study dataset was utilized for validation.Duchenne Natural History Study variables were selected based on clinical relevance to prespecified domains: Cardiac, Pulmonary, Myopathy, Nutrition. Severity points (0-4) were assigned and summed for study visits. MADE score for cohorts defined by age, ambulatory status, and survival were compared at enrollment and longitudinally.Associations between MADE score and mortality were examined.Duchenne Natural History Study enrolled 440 males, 12.6 ±6.1 years old, with 3,559 visits over 4.6 ±2.8 years, 45 deaths. MADE score increased with age and nonambulatory status. Mean MADE score per visit was 19 ±10 for those who died vs. 9.8 ±9.3 in survivors p=0.03. Baseline MADE score >12 predicted mortality independent of age (78% sensitivity, CPE.70). Rising MADE score trajectory was associated with mortality in models adjusted for enrollment age, follow-up time, and ambulatory status, all p<.001.A multiorgan severity score, MADE, was developed to track cumulative morbidities that impact heart failure in Duchenne muscular dystrophy. MADE score predicted Duchenne Natural History Study mortality. MADE score can be used for serial heart failure assessment in males and may serve as an endpoint for Duchenne muscular dystrophy clinical research.

    View details for DOI 10.1016/j.ppedcard.2023.101639

    View details for PubMedID 37990740

    View details for PubMedCentralID PMC10659574

  • Major Adverse Dystrophinopathy Events (MADE) score as marker of cumulative morbidity and risk for mortality in boys with Duchenne muscular dystrophy PROGRESS IN PEDIATRIC CARDIOLOGY Kaufman, B. D., Garcia, A., He, Z., Tesi-Rocha, C., Buu, M., Rosenthal, D., Gordish-Dressman, H., Almond, C. S., Duong, T., CINRG DUCHENNE NAT HIST STUDY 2023; 69
  • Advancing Team-Based Care for Spinal Muscular Atrophy: A Multi-State Project ECHO Initiative and National Education Strategy Gabriel, D., Tesi-Rocha, A., Klotz, J., Adewuya, R., Hack, L., Hess, W. LIPPINCOTT WILLIAMS & WILKINS. 2023
  • Spinal Muscular Atrophy Type 1: Fetal Diagnosis, Prenatal Coordination, and Postnatal Management in the Era of Novel Therapies. NeoReviews Chitkara, R., Chock, V., Davis, A., Rocha, C. T., Day, J. W., Fluharty, B., Hintz, S. 2022; 23 (7): e520-e526

    View details for DOI 10.1542/neo.23-7-e520

    View details for PubMedID 35773512

  • Correction to: Reldesemtiv in Patients with Spinal Muscular Atrophy: a Phase 2 Hypothesis-Generating Study. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics Rudnicki, S. A., Andrews, J. A., Duong, T., Cockroft, B. M., Malik, F. I., Meng, L., Wei, J., Wolff, A. A., Genge, A., Johnson, N. E., Tesi-Rocha, C., Connolly, A. M., Darras, B. T., Felice, K., Finkel, R. S., Shieh, P. B., Mah, J. K., Statland, J., Campbell, C., Habib, A. A., Kuntz, N. L., Oskoui, M., Day, J. W. 2021

    View details for DOI 10.1007/s13311-021-01120-8

    View details for PubMedID 34731415

  • Advances in the therapy of Spinal Muscular Atrophy. The Journal of pediatrics Klotz, J., Rocha, C. T., Young, S. D., Duong, T., Buu, M., Sampson, J., Day, J. W. 2021

    View details for DOI 10.1016/j.jpeds.2021.06.033

    View details for PubMedID 34197889

  • Reldesemtiv in Patients with Spinal Muscular Atrophy: a Phase 2 Hypothesis-Generating Study. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics Rudnicki, S. A., Andrews, J. A., Duong, T. n., Cockroft, B. M., Malik, F. I., Meng, L. n., Wei, J. n., Wolff, A. A., Genge, A. n., Johnson, N. E., Tesi-Rocha, C. n., Connolly, A. M., Darras, B. T., Felice, K. n., Shieh, P. B., Mah, J. K., Statland, J. n., Campbell, C. n., Habib, A. A., Kuntz, N. L., Oskoui, M. n., Day, J. W. 2021


    This phase 2, double-blind, placebo-controlled, hypothesis-generating study evaluated the effects of oral reldesemtiv, a fast skeletal muscle troponin activator, in patients with spinal muscular atrophy (SMA). Patients ≥ 12 years of age with type II, III, or IV SMA were randomized into 2 sequential, ascending reldesemtiv dosing cohorts (cohort 1: 150 mg bid or placebo [2:1]; cohort 2: 450 mg bid or placebo [2:1]). The primary objective was to determine potential pharmacodynamic effects of reldesemtiv on 8 outcome measures in SMA, including 6-minute walk distance (6MWD) and maximum expiratory pressure (MEP). Changes from baseline to weeks 4 and 8 were determined. Pharmacokinetics and safety were also evaluated. Patients were randomized to reldesemtiv 150 mg, 450 mg, or placebo (24, 20, and 26, respectively). The change from baseline in 6MWD was greater for reldesemtiv 450 mg than for placebo at weeks 4 and 8 (least squares [LS] mean difference, 35.6 m [p = 0.0037] and 24.9 m [p = 0.058], respectively). Changes from baseline in MEP at week 8 on reldesemtiv 150 and 450 mg were significantly greater than those on placebo (LS mean differences, 11.7 [p = 0.038] and 13.2 cm H2O [p = 0.03], respectively). For 6MWD and MEP, significant changes from placebo were seen in the highest reldesemtiv peak plasma concentration quartile (Cmax > 3.29 μg/mL; LS mean differences, 43.3 m [p = 0.010] and 28.8 cm H2O [p = 0.0002], respectively). Both dose levels of reldesemtiv were well tolerated. Results suggest reldesemtiv may offer clinical benefit and support evaluation in larger SMA patient populations.

    View details for DOI 10.1007/s13311-020-01004-3

    View details for PubMedID 33624184

  • Knee Strength and Ankle Range of Motion Impacts on Timed Function Tests in Duchenne Muscular Dystrophy: In the Era of Glucocorticoids. Journal of neuromuscular diseases Duong, T., Canbek, J., Fernandez-Fernandez, A., Henricson, E., Birkmeier, M., Siener, C., Rocha, C. T., McDonald, C., Gordish-Dressman, H. 2021


    Duchenne Muscular Dystrophy (DMD) is a neuromuscular disorder that presents in childhood and is characterized by slowly progressive proximal weakness and lower extremity contractures that limit ambulatory ability [1, 2]. Contractures develop in the ankles, knees, and hips due to muscle imbalances, fibrotic changes, loss of strength, and static positioning [2, 5]. Currently, standards of care guidelines emphasize the importance of maintaining good musculoskeletal alignment through stretching, bracing, and glucocorticoid (GC) therapy to preserve strength and function.This is a retrospective analysis of prospectively collected data through the CINRG Duchenne Natural history study (DNHS). The objectives of this analysis are to understand the progression of ankle contractures for individuals with DMD and to investigate the relationship between progressive lower limb contractures, knee strength, and Timed Function Tests.A collection of TFTs including supine to stand (STS), 10 meter walk test (10MWT), and timed stair climbing (4SC) have been used to monitor disease progression and are predictive of loss of ambulation in these patients [4]. Multiple factors contribute to loss of ambulation, including progressive loss of strength and contracture development that leads to changing biomechanical demands for ambulation. A better understanding of the changes in strength and range of motion (ROM) that contribute to loss of function is important in a more individualized rehabilitation management plan. In this longitudinal study, we measured strength using quantitative muscle testing (QMT) with the CINRG Quantitative Measurement System (CQMS)), ROM was measuresed with a goniometer and TFTs were measured using a standard stopwatch and methodology.We enrolled 440 participants; mean baseline age was 8.9 (2.1, 28.0) years with 1321 observations used for analysis. GC use was stratified based on duration on drug with 18.7%at <  6 months or naïve; 4.3%<1 year; 58.0%1 <  10 years; and 19.3%between 10-25 years of GC use. Ankle ROM was better for those on GC compared to GC naive but did not significantly influence long-term progression rates. QMT, ROM, age and GCs contribute to speed of TFTs. Knee extension (KE) strength and Dorsiflexion (DF) ROM are significant predictors of speed for all TFTs (p <  0.001). Of the variables used in this analysis, KE strength is the primary predictor of walking speed, estimating that every pound increase in KE results in a 0.042 m/s improvement in 10MWT, and a smaller similar increase of 0.009 m/s with every degree of ankle DF ROM.GC use provides an improvement in strength and ROM but does not affect rate of change. Knee strength has a greater influence on speed of TFTs than DF ROM, although both are statistically significant predictors of speed. Results show that retaining knee strength [1, 2], along with joint flexibility, may be important factors in the ability to perform walking, climbing and supine to stand activities.

    View details for DOI 10.3233/JND-210724

    View details for PubMedID 34719507

  • TCTEX1D1 is a genetic modifier of disease progression in Duchenne muscular dystrophy. European journal of human genetics : EJHG Spitali, P., Zaharieva, I., Bohringer, S., Hiller, M., Chaouch, A., Roos, A., Scotton, C., Claustres, M., Bello, L., McDonald, C. M., Hoffman, E. P., Koeks, Z., Eka Suchiman, H., Cirak, S., Scoto, M., Reza, M., 't Hoen, P. A., Niks, E. H., Tuffery-Giraud, S., Lochmüller, H., Ferlini, A., Muntoni, F., Aartsma-Rus, A. 2020; 28 (6): 815-825


    Duchenne muscular dystrophy (DMD) is caused by pathogenic variants in the DMD gene leading to the lack of dystrophin. Variability in the disease course suggests that other factors influence disease progression. With this study we aimed to identify genetic factors that may account for some of the variability in the clinical presentation. We compared whole-exome sequencing (WES) data in 27 DMD patients with extreme phenotypes to identify candidate variants that could affect disease progression. Validation of the candidate SNPs was performed in two independent cohorts including 301 (BIO-NMD cohort) and 109 (CINRG cohort of European ancestry) DMD patients, respectively. Variants in the Tctex1 domain containing 1 (TCTEX1D1) gene on chromosome 1 were associated with age of ambulation loss. The minor alleles of two independent variants, known to affect TCTEX1D1 coding sequence and induce skipping of its exon 4, were associated with earlier loss of ambulation. Our data show that disease progression of DMD is affected by a new locus on chromosome 1 and demonstrate the possibility to identify genetic modifiers in rare diseases by studying WES data in patients with extreme phenotypes followed by multiple layers of validation.

    View details for DOI 10.1038/s41431-019-0563-6

    View details for PubMedID 31896777

    View details for PubMedCentralID PMC7253478

  • Genetic modifiers of respiratory function in Duchenne muscular dystrophy. Annals of clinical and translational neurology Bello, L., D'Angelo, G., Villa, M., Fusto, A., Vianello, S., Merlo, B., Sabbatini, D., Barp, A., Gandossini, S., Magri, F., Comi, G. P., Pedemonte, M., Tacchetti, P., Lanzillotta, V., Trucco, F., D'Amico, A., Bertini, E., Astrea, G., Politano, L., Masson, R., Baranello, G., Albamonte, E., De Mattia, E., Rao, F., Sansone, V. A., Previtali, S., Messina, S., Vita, G. L., Berardinelli, A., Mongini, T., Pini, A., Pane, M., Mercuri, E., Vianello, A., Bruno, C., Hoffman, E. P., Morgenroth, L., Gordish-Dressman, H., McDonald, C. M., Pegoraro, E. 2020; 7 (5): 786-798


    Respiratory insufficiency is a major complication of Duchenne muscular dystrophy (DMD). Its progression shows considerable interindividual variability, which has been less thoroughly characterized and understood than in skeletal muscle. We collected pulmonary function testing (PFT) data from a large retrospective cohort followed at Centers collaborating in the Italian DMD Network. Furthermore, we analyzed PFT associations with different DMD mutation types, and with genetic variants in SPP1, LTBP4, CD40, and ACTN3, known to modify skeletal muscle weakness in DMD. Genetic association findings were independently validated in the Cooperative International Neuromuscular Research Group Duchenne Natural History Study (CINRG-DNHS).Generalized estimating equation analysis of 1852 PFTs from 327 Italian DMD patients, over an average follow-up time of 4.5 years, estimated that forced vital capacity (FVC) declined yearly by -4.2%, forced expiratory volume in 1 sec by -5.0%, and peak expiratory flow (PEF) by -2.9%. Glucocorticoid (GC) treatment was associated with higher values of all PFT measures (approximately + 15% across disease stages). Mutations situated 3' of DMD intron 44, thus predicted to alter the expression of short dystrophin isoforms, were associated with lower (approximately -6%) PFT values, a finding independently validated in the CINRG-DNHS. Deletions amenable to skipping of exon 51 and 53 were independently associated with worse PFT outcomes. A meta-analysis of the two cohorts identified detrimental effects of SPP1 rs28357094 and CD40 rs1883832 minor alleles on both FVC and PEF.These findings support GC efficacy in delaying respiratory insufficiency, and will be useful for the design and interpretation of clinical trials focused on respiratory endpoints in DMD.

    View details for DOI 10.1002/acn3.51046

    View details for PubMedID 32343055

    View details for PubMedCentralID PMC7261745

  • Combined Genome Sequencing and RNA Analysis Reveals and Characterizes a Deep Intronic Variant in IGHMBP2 in a Patient With Spinal Muscular Atrophy With Respiratory Distress Type 1. Pediatric neurology Bodle, E. E., Zhu, W. n., Velez-Bartolomei, F. n., Tesi-Rocha, A. n., Liu, P. n., Bernstein, J. A. 2020; 114: 16–20


    Pathogenic variants in the IGHMBP2 gene cause recessive spinal motor neuropathies of variable phenotype, including a predominantly distal motor impairment of Charcot-Marie-Tooth type 2S and the more severe condition of spinal muscular atrophy with respiratory distress type 1 in which infantile respiratory failure predominates.We describe the first reported case of spinal muscular atrophy with respiratory distress type 1 caused by a novel deep intronic variant in IGHMBP2 (NM_002180c.712-610A>G).The variant was detected by whole genome sequencing. Reverse transcription-polymerase chain reaction and complimentary DNA sequencing were used to characterize the impact of the novel variant.This report illustrates the utility in clinical practice of genome sequencing and RNA analysis, compared with exome sequencing alone.

    View details for DOI 10.1016/j.pediatrneurol.2020.09.011

    View details for PubMedID 33189025

  • Medical management of muscle weakness in Duchenne muscular dystrophy. PloS one Rivera, S. R., Jhamb, S. K., Abdel-Hamid, H. Z., Acsadi, G., Brandsema, J., Ciafaloni, E., Darras, B. T., Iannaccone, S. T., Konersman, C. G., Kuntz, N. L., McDonald, C. M., Parsons, J. A., Tesi Rocha, C., Zaidman, C. M., Butterfield, R. J., Connolly, A. M., Mathews, K. D. 2020; 15 (10): e0240687


    INTRODUCTION: Duchenne muscular dystrophy (DMD) is a childhood onset muscular dystrophy leading to shortened life expectancy. There are gaps in published DMD care guidelines regarding recently approved DMD medications and alternative steroid dosing regimens.METHODS: A list of statements about use of currently available therapies for DMD in the United States was developed based on a systematic literature review and expert panel feedback. Panelists' responses were collected using a modified Delphi approach.RESULTS: Among corticosteroid regimens, either deflazacort or prednisone weekend dosing was preferred when payer requirements do not dictate choice. Most patients with exon 51 skip-amenable mutations should be offered eteplirsen, before or with a corticosteroid.DISCUSSION: The options available for medical management of the motor symptoms of DMD are expanding rapidly. The choice of medical therapies should balance expected benefit with side effects.

    View details for DOI 10.1371/journal.pone.0240687

    View details for PubMedID 33075081

  • Towards regulatory endorsement of drug development tools to promote the application of model-informed drug development in Duchenne muscular dystrophy. Journal of pharmacokinetics and pharmacodynamics Conrado, D. J., Larkindale, J., Berg, A., Hill, M., Burton, J., Abrams, K. R., Abresch, R. T., Bronson, A., Chapman, D., Crowther, M., Duong, T., Gordish-Dressman, H., Harnisch, L., Henricson, E., Kim, S., McDonald, C. M., Schmidt, S., Vong, C., Wang, X., Wong, B. L., Yong, F., Romero, K., Duchenne Muscular Dystrophy Regulatory Science Consortium (D-RSC), Vishwanathan, V., Chidambaranathan, S., Douglas Biggar, W., McAdam, L. C., Mah, J. K., Tulinius, M., Cnaan, A., Morgenroth, L. P., Leshner, R., Tesi-Rocha, C., Thangarajh, M., Duong, T., Kornberg, A., Ryan, M., Nevo, Y., Dubrovsky, A., Clemens, P. R., Abdel-Hamid, H., Connolly, A. M., Pestronk, A., Teasley, J., Bertorini, T. E., Webster, R., Kolski, H., Kuntz, N., Driscoll, S., Bodensteiner, J. B., Gorni, K., Lotze, T., Day, J. W., Karachunski, P., Henricson, E. K., Abresch, R. T., Joyce, N. C., McDonald, C. M., McDonald, C. M., Campbell, C., Torricelli, R. E., Finkel, R. S., Flanigan, K. M., Goemans, N., Heydemann, P., Kaminska, A., Kirschner, J., Muntoni, F., Osorio, A. N., Schara, U., Sejersen, T., Shieh, P. B., Sweeney, H. L., Topaloglu, H., Tulinius, M., Vilchez, J. J., Voit, T., Wong, B., Alfano, L. N., Eagle, M., James, M. K., Lowes, L., Mayhew, A., Mazzone, E. S., Nelson, L., Rose, K. J., Abdel-Hamid, H. Z., Apkon, S. D., Barohn, R. J., Bertini, E., Bloetzer, C., deVaud, L. C., Butterfield, R. J., Chabrol, B., Chae, J. H., Jongno-Gu, D. R., Comi, G. P., Darras, B. T., Dastgir, J., Desguerre, I., Escobar, R. G., Finanger, E., Guglieri, M., Hughes, I., Iannaccone, S. T., Jones, K. J., Karachunski, P., Kudr, M., Lotze, T., Mah, J. K., Mathews, K., Nevo, Y., Parsons, J., Pereon, Y., de Queiroz Campos Araujo, A. P., Renfroe, J. B., de Resende, M. B., Ryan, M., Selby, K., Tennekoon, G., Vita, G., Abdel-Hamid, H., Apkon, S., Barohn, R., Belousova, E., Bertini, E., Brandsema, J., Bruno, C., Burnette, W., Butterfield, R., Byrne, B., Campbell, C., Carlo, J., Chae, J. H., Chandratre, S., Comi, G., Connolly, A., De Groot I, I., Deconinck, N., Dooley, J., Dubrovsky, A., Durigneux, J., Finanger, E., Finkel, R., Frank, L. M., Goemans, N., Harper, A., Hattori, A., Herguner, O., Iannaccone, S., Janas, J., Jong, Y. J., Kirschner, J., Komaki, H., Kuntz, N., Lee, W. T., Leung, E., Mah, J., Mathews, K., McDonald, C. M., Mercuri, E., McMillan, H., Mueller-Felber, W., de Munain A, L., Nakamura, A., Niks, E., Ogata, K., Pascual, S., Pegoraro, E., Pereon, Y., Renfroe, B., Sanka, R. B., Schallner, J., Schara, U., Selby, K., Sendra, I. I., Servais, L., Smith, E., Sparks, S., Topaloglu, H., Victor, R., Vilchez, J. J., Wicklund, M., Wilichoswki, E., Wong, B., Abresch, R. T., Carter, G. T., Henricson, E., McDonald, C. M. 2019


    Drug development for rare diseases is challenged by small populations and limited data. This makes development of clinical trial protocols difficult and contributes to the uncertainty around whether or not a potential therapy is efficacious. The use of data standards to aggregate data from multiple sources, and the use of such integrated databases to develop statistical models can inform protocol development and reduce the risks in developing new therapies. Achieving regulatory endorsement of such models through defined pathways at the US Food and Drug Administration and European Medicines Authority allows such tools to be used by the drug development community for defined contexts of use without further need for discussion of the underlying model(s). The Duchenne Regulatory Science Consortium (D-RSC) has brought together multiple stakeholders to develop a clinical trial simulation tool for Duchenne muscular dystrophy using such an approach. Here we describe the work of D-RSC as an example of how such an approach may be effective at reducing uncertainty in drug development for rare diseases, and thus bringing effective therapies to patients faster.

    View details for DOI 10.1007/s10928-019-09642-7

    View details for PubMedID 31127458

  • Chronic Polyneuritis of Childhood JOURNAL OF PEDIATRICS Klotz, J., Rocha, C. 2019; 208: 175
  • Assessment of disease progression in dysferlinopathy: A 1-year cohort study NEUROLOGY Moore, U., Jacobs, M., James, M. K., Mayhew, A. G., Fernandez-Torron, R., Feng, J., Cnaan, A., Eagle, M., Bettinson, K., Rufibach, L. E., Lofra, R., Blamire, A. M., Carlier, P. G., Mittal, P., Lowes, L., Alfano, L., Rose, K., Duong, T., Berry, K. M., Montiel-Morillo, E., Pedrosa-Hernandez, I., Holsten, S., Sanjak, M., Ashida, A., Sakamoto, C., Tateishi, T., Yajima, H., Canal, A., Ollivier, G., Decostre, V., Mendez, J., Praxedes, N., Thiele, S., Siener, C., Shierbecker, J., Florence, J. M., Vandevelde, B., DeWolf, B., Hutchence, M., Gee, R., Pruegel, J., Maron, E., Hilsden, H., Lochmueller, H., Grieben, U., Spuler, S., Rocha, C., Day, J. W., Jones, K. J., Bharucha-Goebel, D. X., Salort-Campana, E., Harms, M., Pestronk, A., Krause, S., Schreiber-Katz, O., Walter, M. C., Paradas, C., Hogrel, J., Stojkovic, T., Takeda, S., Mori-Yoshimura, M., Bravver, E., Sparks, S., Diaz-Manera, J., Bello, L., Semplicini, C., Pegoraro, E., Mendell, J. R., Bushby, K., Straub, V., Arrieta, A., Hwang, E., Lee, E., Illa, I., Gallardo, E., Belmonte Jimeno, I., Llauger Rossello, J., Harwick, B., Sykes, J., Yetter, B., Smith, M., Lapeyssonie, B., Bendahan, D., Le Fur, Y., Shahram, A., Albane, T., Coppenrath, E. M., Harris, E., Guglieri, M., Evangelista, T., Murphy, A., Moat, D., Hodgson, T., Wallace, D., Ward, L., Galley, D., Calore, C., Stramare, R., Rampado, A., Gidaro, T., Turk, S., Servais, L., Theis, C., Diabate, O., Schimmoeller, L., Foster, G., Carbonell, P., Cabrera, M., Morgado, Y., Gala, S., Perez, J., Sawyer, A., Clarke, N. F., Sandaradura, S., Ghaoui, R., Cornett, K., Miller, C., Foster, S., Peduto, A., Sato, N., Tamaru, T., Kobayashi, Y., Ashida, A., Nakayama, T., Segawa, K., Ohtaguro, S., Nakamura, H., Ohhata, M., Kimura, E., Endo, M., Brody, N., Leach, M. E., Toles, A., Fricke, S. T., Otero, H. J., Jain COS Consortium 2019; 92 (5): E461–E474
  • Assessment of disease progression in dysferlinopathy: A 1-year cohort study. Neurology Moore, U., Jacobs, M., James, M. K., Mayhew, A. G., Fernandez-Torron, R., Feng, J., Cnaan, A., Eagle, M., Bettinson, K., Rufibach, L. E., Lofra, R. M., Blamire, A. M., Carlier, P. G., Mittal, P., Lowes, L. P., Alfano, L., Rose, K., Duong, T., Berry, K. M., Montiel-Morillo, E., Pedrosa-Hernandez, I., Holsten, S., Sanjak, M., Ashida, A., Sakamoto, C., Tateishi, T., Yajima, H., Canal, A., Ollivier, G., Decostre, V., Mendez, J. B., Sanchez-Aguilera Praxedes, N., Thiele, S., Siener, C., Shierbecker, J., Florence, J. M., Vandevelde, B., DeWolf, B., Hutchence, M., Gee, R., Prugel, J., Maron, E., Hilsden, H., Lochmuller, H., Grieben, U., Spuler, S., Tesi Rocha, C., Day, J. W., Jones, K. J., Bharucha-Goebel, D. X., Salort-Campana, E., Harms, M., Pestronk, A., Krause, S., Schreiber-Katz, O., Walter, M. C., Paradas, C., Hogrel, J., Stojkovic, T., Takeda, S., Mori-Yoshimura, M., Bravver, E., Sparks, S., Diaz-Manera, J., Bello, L., Semplicini, C., Pegoraro, E., Mendell, J. R., Bushby, K., Straub, V., Jain COS Consortium 2019


    OBJECTIVE: To assess the ability of functional measures to detect disease progression in dysferlinopathy over 6 months and 1 year.METHODS: One hundred ninety-three patients with dysferlinopathy were recruited to the Jain Foundation's International Clinical Outcome Study for Dysferlinopathy. Baseline, 6-month, and 1-year assessments included adapted North Star Ambulatory Assessment (a-NSAA), Motor Function Measure (MFM-20), timed function tests, 6-minute walk test (6MWT), Brooke scale, Jebsen test, manual muscle testing, and hand-held dynamometry. Patients also completed the ACTIVLIM questionnaire. Change in each measure over 6 months and 1 year was calculated and compared between disease severity (ambulant [mild, moderate, or severe based on a-NSAA score] or nonambulant [unable to complete a 10-meter walk]) and clinical diagnosis.RESULTS: The functional a-NSAA test was the most sensitive to deterioration for ambulant patients overall. The a-NSAA score was the most sensitive test in the mild and moderate groups, while the 6MWT was most sensitive in the severe group. The 10-meter walk test was the only test showing significant change across all ambulant severity groups. In nonambulant patients, the MFM domain 3, wrist flexion strength, and pinch grip were most sensitive. Progression rates did not differ by clinical diagnosis. Power calculations determined that 46 moderately affected patients are required to determine clinical effectiveness for a hypothetical 1-year clinical trial based on the a-NSAA as a clinical endpoint.CONCLUSION: Certain functional outcome measures can detect changes over 6 months and 1 year in dysferlinopathy and potentially be useful in monitoring progression in clinical trials.CLINICALTRIALSGOV IDENTIFIER: NCT01676077.

    View details for PubMedID 30626655

  • 50 Years Ago in The Journal of Pediatrics: Chronic Polyneuritis of Childhood. The Journal of pediatrics Klotz, J. n., Tesi Rocha, C. n. 2019; 208: 175

    View details for PubMedID 31027619

  • Teenage exercise is associated with earlier symptom onset in dysferlinopathy: a retrospective cohort study JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY Moore, U. R., Jacobs, M., Fernandez-Torron, R., Jang, J., James, M. K., Mayhew, A., Rufibach, L., Mittal, P., Eagle, M., Cnaan, A., Carlier, P. G., Blamire, A., Hilsden, H., Lochmueller, H., Grieben, U., Spuler, S., Rocha, C., Day, J. W., Jones, K. J., Bharucha-Goebel, D. X., Salort-Campana, E., Harms, M., Pestronk, A., Krause, S., Schreiber-Katz, O., Walter, M. C., Paradas, C., Hogrel, J., Stojkovic, T., Takeda, S., Mori-Yoshimura, M., Bravver, E., Sparks, S., Diaz-Manera, J., Bello, L., Semplicini, C., Pegoraro, E., Mendell, J. R., Bushby, K., Straub, V. 2018; 89 (11): 1224-+
  • Nusinersen versus Sham Control in Later-Onset Spinal Muscular Atrophy NEW ENGLAND JOURNAL OF MEDICINE Mercuri, E., Darras, B. T., Chiriboga, C. A., Day, J. W., Campbell, C., Connolly, A. M., Iannaccone, S. T., Kirschner, J., Kuntz, N. L., Saito, K., Shieh, P. B., Tulinius, M., Mazzone, E. S., Montes, J., Bishop, K. M., Yang, Q., Foster, R., Gheuens, S., Bennett, C. F., Farwell, W., Schneider, E., De Vivo, D. C., Finkel, R. S., CHERISH Study Grp 2018; 378 (7): 625–35


    Nusinersen is an antisense oligonucleotide drug that modulates pre-messenger RNA splicing of the survival motor neuron 2 ( SMN2) gene. It has been developed for the treatment of spinal muscular atrophy (SMA).We conducted a multicenter, double-blind, sham-controlled, phase 3 trial of nusinersen in 126 children with SMA who had symptom onset after 6 months of age. The children were randomly assigned, in a 2:1 ratio, to undergo intrathecal administration of nusinersen at a dose of 12 mg (nusinersen group) or a sham procedure (control group) on days 1, 29, 85, and 274. The primary end point was the least-squares mean change from baseline in the Hammersmith Functional Motor Scale-Expanded (HFMSE) score at 15 months of treatment; HFMSE scores range from 0 to 66, with higher scores indicating better motor function. Secondary end points included the percentage of children with a clinically meaningful increase from baseline in the HFMSE score (≥3 points), an outcome that indicates improvement in at least two motor skills.In the prespecified interim analysis, there was a least-squares mean increase from baseline to month 15 in the HFMSE score in the nusinersen group (by 4.0 points) and a least-squares mean decrease in the control group (by -1.9 points), with a significant between-group difference favoring nusinersen (least-squares mean difference in change, 5.9 points; 95% confidence interval, 3.7 to 8.1; P<0.001). This result prompted early termination of the trial. Results of the final analysis were consistent with results of the interim analysis. In the final analysis, 57% of the children in the nusinersen group as compared with 26% in the control group had an increase from baseline to month 15 in the HFMSE score of at least 3 points (P<0.001), and the overall incidence of adverse events was similar in the nusinersen group and the control group (93% and 100%, respectively).Among children with later-onset SMA, those who received nusinersen had significant and clinically meaningful improvement in motor function as compared with those in the control group. (Funded by Biogen and Ionis Pharmaceuticals; CHERISH number, NCT02292537 .).

    View details for PubMedID 29443664

  • Long-term effects of glucocorticoids on function, quality of life, and survival in patients with Duchenne muscular dystrophy: a prospective cohort study LANCET McDonald, C. M., Henricson, E. K., Abresch, R. T., Duong, T., Joyce, N. C., Hu, F., Clemens, P. R., Hoffman, E. P., Cnaan, A., Gordish-Dressman, H., CINRG Investigators 2018; 391 (10119): 451–61


    Glucocorticoid treatment is recommended as a standard of care in Duchenne muscular dystrophy; however, few studies have assessed the long-term benefits of this treatment. We examined the long-term effects of glucocorticoids on milestone-related disease progression across the lifespan and survival in patients with Duchenne muscular dystrophy.For this prospective cohort study, we enrolled male patients aged 2-28 years with Duchenne muscular dystrophy at 20 centres in nine countries. Patients were followed up for 10 years. We compared no glucocorticoid treatment or cumulative treatment duration of less than 1 month versus treatment of 1 year or longer with regard to progression of nine disease-related and clinically meaningful mobility and upper limb milestones. We used Kaplan-Meier analyses to compare glucocorticoid treatment groups for time to stand from supine of 5 s or longer and 10 s or longer, and loss of stand from supine, four-stair climb, ambulation, full overhead reach, hand-to-mouth function, and hand function. Risk of death was also assessed. This study is registered with, number NCT00468832.440 patients were enrolled during two recruitment periods (2006-09 and 2012-16). Time to all disease progression milestone events was significantly longer in patients treated with glucocorticoids for 1 year or longer than in patients treated for less than 1 month or never treated (log-rank p<0·0001). Glucocorticoid treatment for 1 year or longer was associated with increased median age at loss of mobility milestones by 2·1-4·4 years and upper limb milestones by 2·8-8·0 years compared with treatment for less than 1 month. Deflazacort was associated with increased median age at loss of three milestones by 2·1-2·7 years in comparison with prednisone or prednisolone (log-rank p<0·012). 45 patients died during the 10-year follow-up. 39 (87%) of these deaths were attributable to Duchenne-related causes in patients with known duration of glucocorticoids usage. 28 (9%) deaths occurred in 311 patients treated with glucocorticoids for 1 year or longer compared with 11 (19%) deaths in 58 patients with no history of glucocorticoid use (odds ratio 0·47, 95% CI 0·22-1·00; p=0·0501).In patients with Duchenne muscular dystrophy, glucocorticoid treatment is associated with reduced risk of losing clinically meaningful mobility and upper limb disease progression milestones across the lifespan as well as reduced risk of death.US Department of Education/National Institute on Disability and Rehabilitation Research; US Department of Defense; National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases; and Parent Project Muscular Dystrophy.

    View details for DOI 10.1016/S0140-6736(17)32160-8

    View details for Web of Science ID 000424333600034

    View details for PubMedID 29174484

  • Muscle MRI in patients with dysferlinopathy: pattern recognition and implications for clinical trials. Journal of neurology, neurosurgery, and psychiatry Diaz-Manera, J. n., Fernandez-Torron, R. n., LLauger, J. n., James, M. K., Mayhew, A. n., Smith, F. E., Moore, U. R., Blamire, A. M., Carlier, P. G., Rufibach, L. n., Mittal, P. n., Eagle, M. n., Jacobs, M. n., Hodgson, T. n., Wallace, D. n., Ward, L. n., Smith, M. n., Stramare, R. n., Rampado, A. n., Sato, N. n., Tamaru, T. n., Harwick, B. n., Rico Gala, S. n., Turk, S. n., Coppenrath, E. M., Foster, G. n., Bendahan, D. n., Le Fur, Y. n., Fricke, S. T., Otero, H. n., Foster, S. L., Peduto, A. n., Sawyer, A. M., Hilsden, H. n., Lochmuller, H. n., Grieben, U. n., Spuler, S. n., Tesi Rocha, C. n., Day, J. W., Jones, K. J., Bharucha-Goebel, D. X., Salort-Campana, E. n., Harms, M. n., Pestronk, A. n., Krause, S. n., Schreiber-Katz, O. n., Walter, M. C., Paradas, C. n., Hogrel, J. Y., Stojkovic, T. n., Takeda, S. n., Mori-Yoshimura, M. n., Bravver, E. n., Sparks, S. n., Bello, L. n., Semplicini, C. n., Pegoraro, E. n., Mendell, J. R., Bushby, K. n., Straub, V. n. 2018


    Dysferlinopathies are a group of muscle disorders caused by mutations in the DYSF gene. Previous muscle imaging studies describe a selective pattern of muscle involvement in smaller patient cohorts, but a large imaging study across the entire spectrum of the dysferlinopathies had not been performed and previous imaging findings were not correlated with functional tests.We present cross-sectional T1-weighted muscle MRI data from 182 patients with genetically confirmed dysferlinopathies. We have analysed the pattern of muscles involved in the disease using hierarchical analysis and presented it as heatmaps. Results of the MRI scans have been correlated with relevant functional tests for each region of the body analysed.In 181 of the 182 patients scanned, we observed muscle pathology on T1-weighted images, with the gastrocnemius medialis and the soleus being the most commonly affected muscles. A similar pattern of involvement was identified in most patients regardless of their clinical presentation. Increased muscle pathology on MRI correlated positively with disease duration and functional impairment.The information generated by this study is of high diagnostic value and important for clinical trial development. We have been able to describe a pattern that can be considered as characteristic of dysferlinopathy. We have defined the natural history of the disease from a radiological point of view. These results enabled the identification of the most relevant regions of interest for quantitative MRI in longitudinal studies, such as clinical trials.NCT01676077.

    View details for PubMedID 29735511

  • Teenage exercise is associated with earlier symptom onset in dysferlinopathy: a retrospective cohort study. Journal of neurology, neurosurgery, and psychiatry Moore, U. R., Jacobs, M. n., Fernandez-Torron, R. n., Jang, J. n., James, M. K., Mayhew, A. n., Rufibach, L. n., Mittal, P. n., Eagle, M. n., Cnaan, A. n., Carlier, P. G., Blamire, A. n., Hilsden, H. n., Lochmüller, H. n., Grieben, U. n., Spuler, S. n., Tesi Rocha, C. n., Day, J. W., Jones, K. J., Bharucha-Goebel, D. X., Salort-Campana, E. n., Harms, M. n., Pestronk, A. n., Krause, S. n., Schreiber-Katz, O. n., Walter, M. C., Paradas, C. n., Hogrel, J. Y., Stojkovic, T. n., Takeda, S. n., Mori-Yoshimura, M. n., Bravver, E. n., Sparks, S. n., Diaz-Manera, J. n., Bello, L. n., Semplicini, C. n., Pegoraro, E. n., Mendell, J. R., Bushby, K. n., Straub, V. n. 2018

    View details for PubMedID 29378789

  • Loss-of-Function Mutations in LGI4, a Secreted Ligand Involved in Schwann Cell Myelination, Are Responsible for Arthrogryposis Multiplex Congenita AMERICAN JOURNAL OF HUMAN GENETICS Xue, S., Maluenda, J., Marguet, F., Shboul, M., Quevarec, L., Bonnard, C., Ng, A. Y., Tohari, S., Thong Teck Tan, T. T., Kong, M. K., Monaghan, K. G., Cho, M. T., Siskind, C. E., Sampson, J. B., Rocha, C. T., Alkazaleh, F., Gonzales, M., Rigonnot, L., Whalen, S., Gut, M., Gut, I., Bucourt, M., Venkatesh, B., Laquerriere, A., Reversade, B., Melki, J. 2017; 100 (4): 659-665


    Arthrogryposis multiplex congenita (AMC) is a developmental condition characterized by multiple joint contractures resulting from reduced or absent fetal movements. Through genetic mapping of disease loci and whole-exome sequencing in four unrelated multiplex families presenting with severe AMC, we identified biallelic loss-of-function mutations in LGI4 (leucine-rich glioma-inactivated 4). LGI4 is a ligand secreted by Schwann cells that regulates peripheral nerve myelination via its cognate receptor ADAM22 expressed by neurons. Immunolabeling experiments and transmission electron microscopy of the sciatic nerve from one of the affected individuals revealed a lack of myelin. Functional tests using affected individual-derived iPSCs showed that these germline mutations caused aberrant splicing of the endogenous LGI4 transcript and in a cell-based assay impaired the secretion of truncated LGI4 protein. This is consistent with previous studies reporting arthrogryposis in Lgi4-deficient mice due to peripheral hypomyelination. This study adds to the recent reports implicating defective axoglial function as a key cause of AMC.

    View details for DOI 10.1016/j.ajhg.2017.02.006

    View details for PubMedID 28318499

  • Evidence for ACTN3 as a genetic modifier of Duchenne muscular dystrophy NATURE COMMUNICATIONS Hogarth, M. W., Houweling, P. J., Thomas, K. C., Gordish-Dressman, H., Bello, L., Pegoraro, E., Hoffman, E. P., Head, S. I., North, K. N. 2017; 8


    Duchenne muscular dystrophy (DMD) is characterized by muscle degeneration and progressive weakness. There is considerable inter-patient variability in disease onset and progression, which can confound the results of clinical trials. Here we show that a common null polymorphism (R577X) in ACTN3 results in significantly reduced muscle strength and a longer 10 m walk test time in young, ambulant patients with DMD; both of which are primary outcome measures in clinical trials. We have developed a double knockout mouse model, which also shows reduced muscle strength, but is protected from stretch-induced eccentric damage with age. This suggests that α-actinin-3 deficiency reduces muscle performance at baseline, but ameliorates the progression of dystrophic pathology. Mechanistically, we show that α-actinin-3 deficiency triggers an increase in oxidative muscle metabolism through activation of calcineurin, which likely confers the protective effect. Our studies suggest that ACTN3 R577X genotype is a modifier of clinical phenotype in DMD patients.

    View details for DOI 10.1038/ncomms14143

    View details for Web of Science ID 000393097000001

    View details for PubMedID 28139640

    View details for PubMedCentralID PMC5290331

  • Nusinersen versus Sham Control in Infantile-Onset Spinal Muscular Atrophy. The New England journal of medicine Finkel, R. S., Mercuri, E. n., Darras, B. T., Connolly, A. M., Kuntz, N. L., Kirschner, J. n., Chiriboga, C. A., Saito, K. n., Servais, L. n., Tizzano, E. n., Topaloglu, H. n., Tulinius, M. n., Montes, J. n., Glanzman, A. M., Bishop, K. n., Zhong, Z. J., Gheuens, S. n., Bennett, C. F., Schneider, E. n., Farwell, W. n., De Vivo, D. C. 2017; 377 (18): 1723–32


    Spinal muscular atrophy is an autosomal recessive neuromuscular disorder that is caused by an insufficient level of survival motor neuron (SMN) protein. Nusinersen is an antisense oligonucleotide drug that modifies pre-messenger RNA splicing of the SMN2 gene and thus promotes increased production of full-length SMN protein.We conducted a randomized, double-blind, sham-controlled, phase 3 efficacy and safety trial of nusinersen in infants with spinal muscular atrophy. The primary end points were a motor-milestone response (defined according to results on the Hammersmith Infant Neurological Examination) and event-free survival (time to death or the use of permanent assisted ventilation). Secondary end points included overall survival and subgroup analyses of event-free survival according to disease duration at screening. Only the first primary end point was tested in a prespecified interim analysis. To control the overall type I error rate at 0.05, a hierarchical testing strategy was used for the second primary end point and the secondary end points in the final analysis.In the interim analysis, a significantly higher percentage of infants in the nusinersen group than in the control group had a motor-milestone response (21 of 51 infants [41%] vs. 0 of 27 [0%], P<0.001), and this result prompted early termination of the trial. In the final analysis, a significantly higher percentage of infants in the nusinersen group than in the control group had a motor-milestone response (37 of 73 infants [51%] vs. 0 of 37 [0%]), and the likelihood of event-free survival was higher in the nusinersen group than in the control group (hazard ratio for death or the use of permanent assisted ventilation, 0.53; P=0.005). The likelihood of overall survival was higher in the nusinersen group than in the control group (hazard ratio for death, 0.37; P=0.004), and infants with a shorter disease duration at screening were more likely than those with a longer disease duration to benefit from nusinersen. The incidence and severity of adverse events were similar in the two groups.Among infants with spinal muscular atrophy, those who received nusinersen were more likely to be alive and have improvements in motor function than those in the control group. Early treatment may be necessary to maximize the benefit of the drug. (Funded by Biogen and Ionis Pharmaceuticals; ENDEAR number, NCT02193074 .).

    View details for DOI 10.1056/NEJMoa1702752

    View details for PubMedID 29091570

  • Targeted Re-Sequencing Emulsion PCR Panel for Myopathies: Results in 94 Cases. Journal of neuromuscular diseases Punetha, J., Kesari, A., Uapinyoying, P., Giri, M., Clarke, N. F., Waddell, L. B., North, K. N., Ghaoui, R., O'Grady, G. L., Oates, E. C., Sandaradura, S. A., Bönnemann, C. G., Donkervoort, S., Plotz, P. H., Smith, E. C., Tesi-Rocha, C., Bertorini, T. E., Tarnopolsky, M. A., Reitter, B., Hausmanowa-Petrusewicz, I., Hoffman, E. P. 2016; 3 (2): 209-225


    Molecular diagnostics in the genetic myopathies often requires testing of the largest and most complex transcript units in the human genome (DMD, TTN, NEB). Iteratively targeting single genes for sequencing has traditionally entailed high costs and long turnaround times. Exome sequencing has begun to supplant single targeted genes, but there are concerns regarding coverage and needed depth of the very large and complex genes that frequently cause myopathies.To evaluate efficiency of next-generation sequencing technologies to provide molecular diagnostics for patients with previously undiagnosed myopathies.We tested a targeted re-sequencing approach, using a 45 gene emulsion PCR myopathy panel, with subsequent sequencing on the Illumina platform in 94 undiagnosed patients. We compared the targeted re-sequencing approach to exome sequencing for 10 of these patients studied.We detected likely pathogenic mutations in 33 out of 94 patients with a molecular diagnostic rate of approximately 35%. The remaining patients showed variants of unknown significance (35/94 patients) or no mutations detected in the 45 genes tested (26/94 patients). Mutation detection rates for targeted re-sequencing vs. whole exome were similar in both methods; however exome sequencing showed better distribution of reads and fewer exon dropouts.Given that costs of highly parallel re-sequencing and whole exome sequencing are similar, and that exome sequencing now takes considerably less laboratory processing time than targeted re-sequencing, we recommend exome sequencing as the standard approach for molecular diagnostics of myopathies.

    View details for PubMedID 27854218

  • 50 Years Ago in THE JOURNAL OF PEDIATRICS Myotonic Dystrophy: A Neglected Form of Mental Retardation JOURNAL OF PEDIATRICS Rocha, C. T. 2016; 170: 112-112

    View details for DOI 10.1016/j.jpeds.2015.10.023

    View details for Web of Science ID 000370820500025

    View details for PubMedID 26922763

  • Exome Sequencing Identifies DYNC1H1 Variant Associated With Vertebral Abnormality and Spinal Muscular Atrophy With Lower Extremity Predominance. Pediatric neurology Punetha, J., Monges, S., Franchi, M. E., Hoffman, E. P., Cirak, S., Tesi-Rocha, C. 2015; 52 (2): 239-244


    Molecular diagnosis of the distal spinal muscular atrophies or distal hereditary motor neuropathies remains challenging because of clinical and genetic heterogeneity. Next generation sequencing offers potential for identifying de novo mutations of causative genes in isolated cases.We present a 3.6-year-old girl with congenital scoliosis, equinovarus, and L5/S1 left hemivertebra who demonstrated delayed walking and lower extremities atrophy. She was negative for SMN1 deletion testing, and parents show no sign of disease.Whole exome sequencing of the affected girl showed a novel de novo heterozygous missense mutation c.1792C>T (p.Arg598Cys) in the tail domain of the DYNC1H1 gene encoding for cytoplasmic dynein heavy chain 1. The mutation changed a highly conserved amino acid and was absent from both parents.De novo mutations of DYNC1H1 have been found in individuals with autosomal dominant mental retardation with neuronal migration defects. Dominantly inherited mutations of DYNC1H1 have been reported to cause spinal muscular atrophy with predominance of lower extremity involvement and Charcot-Marie-Tooth type 2O. This is the first report of a de novoDYNC1H1 mutation associated with the spinal muscular atrophy with predominance of lower extremity phenotype with a spinal deformity (lumbar hemivertebrae). This case also demonstrates the power of next generation sequencing to discover de novo mutations on a genome-wide scale.

    View details for DOI 10.1016/j.pediatrneurol.2014.09.003

    View details for PubMedID 25484024

    View details for PubMedCentralID PMC4351714



    Cardiomyopathy is a common cause of morbidity and death in patients with Duchenne muscular dystrophy (DMD).This investigation was a cross-sectional cross-sectional analysis of clinical data from the multi-institutional Cooperative International Neuromuscular Research Group (CINRG) DMD Natural History Study of 340 DMD patients aged 2-28 years. Cardiomyopathy was defined as shortening fraction (SF) <28% or ejection fraction (EF) <55%.Two hundred thirty-one participants reported a prior clinical echocardiogram study, and 174 had data for SF or EF. The prevalence of cardiomyopathy was 27% (47 of 174), and it was associated significantly with age and clinical stage. The association of cardiomyopathy with age and clinical stage was not changed by glucocorticoid use as a covariate (P > 0.68). In patients with cardiomyopathy, 57% (27 of 47) reported not taking any cardiac medications. Cardiac medications were used in 12% (15 of 127) of patients without cardiomyopathy.We found that echocardiograms were underutilized, and cardiomyopathy was undertreated in this DMD natural history cohort.

    View details for DOI 10.1002/mus.24163

    View details for Web of Science ID 000340237500014

    View details for PubMedID 24395289

    View details for PubMedCentralID PMC4081523

  • Novel large deletion in the ACTA1 gene in a child with autosomal recessive nemaline myopathy NEUROMUSCULAR DISORDERS Friedman, B., Simpson, K., Tesi-Rocha, C., Zhou, D., Palmer, C. A., Suchy, S. F. 2014; 24 (4): 331-334


    Nemaline myopathy (NM) is a genetically and clinically heterogeneous disorder resulting from a disruption of the thin filament proteins of the striated muscle sarcomere. The disorder is typically characterized by muscle weakness including the face, neck, respiratory, and limb muscles and is clinically classified based on the age of onset and severity. Mutations in the ACTA1 gene contribute to a significant proportion of NM cases. The majority of ACTA1 gene mutations are missense mutations causing autosomal dominant NM by producing an abnormal protein. However, approximately 10% of ACTA1 gene mutations are associated with autosomal recessive NM; these mutations are associated with loss of protein function. We report the first case of a large deletion in the ACTA1 gene contributing to autosomal recessive NM. This case illustrates the importance of understanding disease mechanisms at the molecular level to accurately infer the inheritance pattern and potentially aid with clinical management.

    View details for DOI 10.1016/j.nmd.2013.12.006

    View details for Web of Science ID 000334135200005

    View details for PubMedID 24447884

  • 'Double trouble': diagnostic challenges in Duchenne muscular dystrophy in patients with an additional hereditary skeletal dysplasia. Neuromuscular disorders Donkervoort, S., Schindler, A., Tesi-Rocha, C., Schreiber, A., Leach, M. E., Dastgir, J., Hu, Y., Mankodi, A., Wagner, K. R., Friedman, N. R., Bönnemann, C. G. 2013; 23 (12): 955-961


    Duchenne muscular dystrophy (DMD) is caused by mutations in Dystrophin and affects 1 in 3600-6000 males. It is characterized by progressive weakness leading to loss of ambulation, respiratory insufficiency, cardiomyopathy, and scoliosis. We describe the unusual phenotype of 3 patients with skeletal dysplasias in whom an additional diagnosis of DMD was later established. Two unrelated boys presented with osteogenesis imperfecta due to point mutations in COL1A1 and were both subsequently found to have a 1 bp frameshift deletion in the Dystrophin gene at age 3 and age 15 years, respectively. The third patient had a diagnosis of pseudoachondroplasia caused by a mutation in the COMP gene and was found to have a deletion of exons 48-50 in Dystrophin at age 9. We discuss the atypical presentation caused by the concomitant presence of 2 conditions affecting the musculoskeletal system, emphasizing aspects that may confound the presentation of a well-characterized disease like DMD. Additional series of patients with DMD and a secondary inherited condition are necessary to establish the natural history in this "double trouble" population. The recognition and accurate diagnosis of patients with two independent genetic disease processes is essential for management, prognosis, genetic risk assessment, and discussion regarding potential therapeutic interventions.

    View details for DOI 10.1016/j.nmd.2013.08.003

    View details for PubMedID 24070816

  • The cooperative international neuromuscular research group Duchenne natural history study: Glucocorticoid treatment preserves clinically meaningful functional milestones and reduces rate of disease progression as measured by manual muscle testing and other commonly used clinical trial outcome measures MUSCLE & NERVE Henricson, E. K., Abresch, R. T., Cnaan, A., Hu, F., Duong, T., Arrieta, A., Han, J., Escolar, D. M., Florence, J. M., Clemens, P. R., Hoffman, E. P., McDonald, C. M. 2013; 48 (1): 55-67


    introduction: Glucocorticoid (GC) therapy in Duchenne muscular dystrophy (DMD) has altered disease progression, necessitating contemporary natural history studies.The Cooperative Neuromuscular Research Group (CINRG) DMD Natural History Study (DMD-NHS) enrolled 340 DMD males, ages 2-28 years. A comprehensive battery of measures was obtained.A novel composite functional "milestone" scale scale showed clinically meaningful mobility and upper limb abilities were significantly preserved in GC-treated adolescents/young adults. Manual muscle test (MMT)-based calculations of global strength showed that those patients <10 years of age treated with steroids declined by 0.4 ± 0.39 MMT unit/year, compared with -0.4 ± 0.39 MMT unit/year in historical steroid-naive subjects. Pulmonary function tests (PFTs) were relatively preserved in steroid-treated adolescents. The linearity and magnitude of decline in measures were affected by maturational changes and functional status.In DMD, long-term use of GCs showed reduced strength loss and preserved functional capabilities and PFTs compared with previous natural history studies performed prior to the widespread use of GC therapy.

    View details for DOI 10.1002/mus.23808

    View details for Web of Science ID 000320787700006

    View details for PubMedID 23649481

    View details for PubMedCentralID PMC4103170

  • Pentoxifylline as a rescue treatment for DMD A randomized double-blind clinical trial NEUROLOGY Escolar, D. M., Zimmerman, A., Bertorini, T., Clemens, P. R., Connolly, A. M., Mesa, L., Gorni, K., Kornberg, A., Kolski, H., Kuntz, N., Nevo, Y., Tesi-Rocha, C., Nagaraju, K., Rayavarapu, S., Hache, L. P., Mayhew, J. E., Florence, J., Hu, F., Arrieta, A., Henricson, E., Leshner, R. T., Mah, J. K. 2012; 78 (12): 904-913


    To determine whether pentoxifylline (PTX) slows the decline of muscle strength and function in ambulatory boys with Duchenne muscular dystrophy (DMD).This was a multicenter, randomized, double-blinded, controlled trial comparing 12 months of daily treatment with PTX or placebo in corticosteroid-treated boys with DMD using a slow-release PTX formulation (~20 mg/kg/day). The primary outcome was the change in mean total quantitative muscle testing (QMT) score. Secondary outcomes included changes in QMT subscales, manual muscle strength, pulmonary function, and timed function tests. Outcomes were compared using Student t tests and a linear mixed-effects model. Adverse events (AEs) were compared using the Fisher exact test.A total of 64 boys with DMD with a mean age of 9.9 ± 2.9 years were randomly assigned to PTX or placebo in 11 participating Cooperative International Neuromuscular Research Group centers. There was no significant difference between PTX and the placebo group in total QMT scores (p = 0.14) or in most of the secondary outcomes after a 12-month treatment. The use of PTX was associated with mild to moderate gastrointestinal or hematologic AEs.The addition of PTX to corticosteroid-treated boys with DMD at a moderate to late ambulatory stage of disease did not improve or halt the deterioration of muscle strength and function over a 12-month study period.This study provides Class I evidence that treatment with PTX does not prevent deterioration in muscle function or strength in corticosteroid-treated boys with DMD.

    View details for Web of Science ID 000301937700014

    View details for PubMedID 22402864

    View details for PubMedCentralID PMC3306159

  • LIQUID FORMULATION OF PENTOXIFYLLINE IS A POORLY TOLERATED TREATMENT FOR DUCHENNE DYSTROPHY MUSCLE & NERVE Zimmerman, A., Clemens, P. R., Tesi-Rocha, C., Connolly, A., Iannaccone, S. T., Kuntz, N., Arrieta, A., Hache, L., Henricson, E., Hu, F., Mayhew, J., Escolar, D. M. 2011; 44 (2): 170-173


    In this study we performed an open-label, pilot study of an orally administered liquid formulation of immediate-release pentoxifylline (PTX) on patients with Duchenne muscular dystrophy (DMD). Treatment efficacy, safety, and tolerability were assessed.The tolerability and safety of PTX and measures of muscle strength and function were evaluated during 12 months of treatment.Seventeen boys with DMD, between 4 and 8 years of age, were enrolled at one of five Cooperative International Neuromuscular Research Group (CINRG) centers. Only 9 were able to complete the 12-month PTX treatment phase; the primary reason for discontinuation was adverse events. Intolerable gastrointestinal side effects were experienced by 65% of participants. Two participants had severe leukopenia that resolved with medication withdrawal.Open-label treatment with a liquid formulation of immediate-release PTX resulted in a high incidence of adverse events in boys with DMD. Poor tolerability of this PTX formulation precluded adequate assessment of efficacy.

    View details for DOI 10.1002/mus.22127

    View details for Web of Science ID 000293383700003

    View details for PubMedID 21674534

    View details for PubMedCentralID PMC3136640

  • SPP1 genotype is a determinant of disease severity in Duchenne muscular dystrophy NEUROLOGY Pegoraro, E., Hoffman, E. P., Piva, L., Gavassini, B. F., Cagnin, S., Ermani, M., Bello, L., Soraru, G., Pacchioni, B., Bonifati, M. D., Lanfranchi, G., Angelini, C., Kesari, A., Lee, I., Gordish-Dressman, H., Devaney, J. M., McDonald, C. M. 2011; 76 (3): 219-226


    Duchenne muscular dystrophy (DMD) is the most common single-gene lethal disorder. Substantial patient-patient variability in disease onset and progression and response to glucocorticoids is seen, suggesting genetic or environmental modifiers.Two DMD cohorts were used as test and validation groups to define genetic modifiers: a Padova longitudinal cohort (n = 106) and the Cooperative International Neuromuscular Research Group (CINRG) cross-sectional natural history cohort (n = 156). Single nucleotide polymorphisms to be genotyped were selected from mRNA profiling in patients with severe vs mild DMD, and genome-wide association studies in metabolism and polymorphisms influencing muscle phenotypes in normal volunteers were studied.Effects on both disease progression and response to glucocorticoids were observed with polymorphism rs28357094 in the gene promoter of SPP1 (osteopontin). The G allele (dominant model; 35% of subjects) was associated with more rapid progression (Padova cohort log rank p = 0.003), and 12%-19% less grip strength (CINRG cohort p = 0.0003).Osteopontin genotype is a genetic modifier of disease severity in Duchenne dystrophy. Inclusion of genotype data as a covariate or in inclusion criteria in DMD clinical trials would reduce intersubject variance, and increase sensitivity of the trials, particularly in older subjects.

    View details for Web of Science ID 000286371900007

    View details for PubMedID 21178099

    View details for PubMedCentralID PMC3034396

  • Limb-Girdle and Congenital Muscular Dystrophies: Current Diagnostics, Management, and Emerging Technologies CURRENT NEUROLOGY AND NEUROSCIENCE REPORTS Rocha, C. T., Hoffman, E. P. 2010; 10 (4): 267-276


    The muscular dystrophies show muscle degeneration and regeneration (necrotizing myopathy) on muscle biopsy, typically associated with elevated serum creatine kinase, and muscle weakness. In 1986, the first causative gene was identified for the most prevalent and best-characterized form of muscular dystrophy, Duchenne muscular dystrophy. Over the past 25 years, the number of other genes determined to cause different subtypes has grown rapidly. This review gives a synopsis of the 45 genetically defined types of muscular dystrophies and describes the clinical, pathologic, and molecular aspects of each disease. DNA diagnosis remains the most sensitive and specific method for differential diagnosis, but molecular diagnostics can be expensive and complex (because of multiple genes at multiple testing facilities) and reimbursement may be challenging to obtain. However, emerging DNA sequencing technologies (eg, single-molecule third-generation sequencing units) promise to dramatically reduce the complexity and costs of DNA diagnostics. Treatment for nearly all forms remains supportive and is aimed at preventing complications. However, several promising approaches have entered clinical trials, providing tangible hope that quality of life will improve for many patients in the near future.

    View details for DOI 10.1007/s11910-010-0119-1

    View details for Web of Science ID 000278111800003

    View details for PubMedID 20467841

    View details for PubMedCentralID PMC4079458

  • PPAR alpha L162V underlies variation in serum triglycerides and subcutaneous fat volume in young males BMC MEDICAL GENETICS Uthurralt, J., Gordish-Dressman, H., Bradbury, M., Tesi-Rocha, C., Devaney, J., Harmon, B., Reeves, E. K., Brandoli, C., Hansen, B. C., Seip, R. L., Thompson, P. D., Price, T. B., Angelopoulos, T. J., Clarkson, P. M., Moyna, N. M., Pescatello, L. S., Visich, P. S., Zoeller, R. F., Gordon, P. M., Hoffman, E. P. 2007; 8


    Of the five sub-phenotypes defining metabolic syndrome, all are known to have strong genetic components (typically 50-80% of population variation). Studies defining genetic predispositions have typically focused on older populations with metabolic syndrome and/or type 2 diabetes. We hypothesized that the study of younger populations would mitigate many confounding variables, and allow us to better define genetic predisposition loci for metabolic syndrome.We studied 610 young adult volunteers (average age 24 yrs) for metabolic syndrome markers, and volumetric MRI of upper arm muscle, bone, and fat pre- and post-unilateral resistance training.We found the PPARalpha L162V polymorphism to be a strong determinant of serum triglyceride levels in young White males, where carriers of the V allele showed 78% increase in triglycerides relative to L homozygotes (LL = 116 +/- 11 mg/dL, LV = 208 +/- 30 mg/dL; p = 0.004). Men with the V allele showed lower HDL (LL = 42 +/- 1 mg/dL, LV = 34 +/- 2 mg/dL; p = 0.001), but women did not. Subcutaneous fat volume was higher in males carrying the V allele, however, exercise training increased fat volume of the untrained arm in V carriers, while LL genotypes significantly decreased in fat volume (LL = -1,707 +/- 21 mm3, LV = 17,617 +/- 58 mm3 ; p = 0.002), indicating a systemic effect of the V allele on adiposity after unilateral training. Our study suggests that the primary effect of PPARalpha L162V is on serum triglycerides, with downstream effects on adiposity and response to training.Our results on association of PPARalpha and triglycerides in males showed a much larger effect of the V allele than previously reported in older and less healthy populations. Specifically, we showed the V allele to increase triglycerides by 78% (p = 0.004), and this single polymorphism accounted for 3.8% of all variation in serum triglycerides in males (p = 0.0037).

    View details for DOI 10.1186/1471-2350-8-55

    View details for Web of Science ID 000250533300001

    View details for PubMedID 17705849

    View details for PubMedCentralID PMC2040140

  • CINRG randomized controlled trial of creatine and glutamine in Duchenne muscular dystrophy ANNALS OF NEUROLOGY Escolar, D. M., Buyse, G., Henricson, E., Leshner, R., Florence, J., Mayhew, J., Tesi-Rocha, C., Gorni, K., Pasquali, L., Patel, K. M., McCarter, R., Huang, J., Mayhew, T., Bertorini, T., Carlo, J., Connolly, A. M., Clemens, P. R., Goemans, N., Iannaccone, S. T., Igarashi, M., Nevo, Y., Pestronk, A., Subramony, S. H., Vedanarayanan, V. V., Wessel, H. 2005; 58 (1): 151-155


    We tested the efficacy and safety of glutamine (0.6 gm/kg/day) and creatine (5 gm/day) in 50 ambulant boys with Duchenne muscular dystrophy in a 6-month, double-blind, placebo-controlled clinical trial. Drug efficacy was tested by measuring muscle strength manually (34 muscle groups) and quantitatively (10 muscle groups). Timed functional tests, functional parameters, and pulmonary function tests were secondary outcome measures. Although there was no statistically significant effect of either therapy based on manual and quantitative measurements of muscle strength, a disease-modifying effect of creatine in older Duchenne muscular dystrophy and creatine and glutamine in younger Duchenne muscular dystrophy cannot be excluded. Creatine and glutamine were well tolerated.

    View details for DOI 10.1002/ana.20523

    View details for Web of Science ID 000230287900018

    View details for PubMedID 15984021

  • Update on diagnosis and treatment of hereditary and acquired polyneuropathies in childhood. Supplements to Clinical neurophysiology Rocha, C. T., Escolar, D. M. 2004; 57: 255-271

    View details for PubMedID 16106624

  • Drop episodes in Coffin-Lowry syndrome: an unusual type of startle response EPILEPTIC DISORDERS Caraballo, R., Rocha, A. T., Medina, C., Fejerman, N. 2000; 2 (3): 173-176


    We present a patient with a complete Coffin-Lowry syndrome, associated with drop episodes precipitated by sudden auditory stimuli, which provoked in turn, a definite loss of muscle tone in both legs. Electrophysiological studies showed that these episodes are an unusual type of startle response and that they may be associated with Coffin-Lowry syndrome.

    View details for Web of Science ID 000089792500007

    View details for PubMedID 11022143